Genotype-Specific Genomic Markers Associated with Primary Hepatomas, Based on Complete Genomic Sequencing of Hepatitis B Virus

Abstract

We aimed to identify genomic markers in hepatitis B virus (HBV) that are associated with hepatocellular carcinoma (HCC) development by comparing the complete genomic sequences of HBVs among patients with HCC and those without. One hundred patients with HBV-related HCC and 100 age-matched HBV-infected non-HCC patients (controls) were studied. HBV DNA from serum was directly sequenced to study the whole viral genome. Data mining and rule learning were employed to develop diagnostic algorithms. An independent cohort of 132 cases (43 HCC and 89 non-HCC) was used to validate the accuracy of these algorithms. Among the 100 cases of HCC, 37 had genotype B (all subgenotype Ba) and 63 had genotype C (16 subgenotype Ce and 47 subgenotype Cs) HBV infection. In the control group, 51 had genotype B and 49 had genotype C (10 subgenotype Ce and 39 subgenotype Cs) HBV infection. Genomic algorithms associated with HCC were derived based on genotype/subgenotype-specific mutations. In genotype B HBV, mutations C1165T, A1762T and G1764A, T2712C/A/G, and A/T2525C were associated with HCC. HCC-related mutations T31C, T53C, and A1499G were associated with HBV subgenotype Ce, and mutations G1613A, G1899A, T2170C/G, and T2441C were associated with HBV subgenotype Cs. Amino acid changes caused by these mutations were found in the X, envelope, and precore/core regions in association with HBV genotype B, Ce, and Cs, respectively. In conclusion, infections with different genotypes of HBV (B, Ce, and Cs) carry different genomic markers for HCC at different parts of the HBV genome. Different HBV genotypes may have different virologic mechanisms of hepatocarcinogenesis.

Nucleotide changes related to hepatocellular carcinoma in the enhancer 1/x‐promoter of hepatitis B virus subgenotype C2 in cirrhotic patients

“…Another study reported a nucleotide mutation related to HCC at nt.1165 in genotype B. (24) Although our study also found a greater number of nucleotide mutations in the HCC group (LC vs LC-HCC, 2 vs 6), the difference was statistically insignificant. The difference in the genotype is probably responsible for the different results, but a further study with more subjects is needed.…”

“…It is possible for nucleotide mutations to occur at the same site, but their functions differ for each genotype. (24) These results suggest that the viral genotype, HBx expression levels, and underlying conditions of the host are important for hepatocarcinogenesis. Thus, further study is required to elucidate the correlation between hepatocarcinogenesis by HBV and the expression of HBx in similar conditions.…”

Distribution and Hepatocellular Carcinoma–Related Viral Properties of Hepatitis B Virus Genotypes in Mainland China: A Community-Based Study

“…HBeAg expression and high viral load are associated with an increased risk of HCC (18,19). Some mutations in the PreS and the EnhII/BCP/Precore regions have been associated with the development of HCC (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Our recent meta-analysis using published data up to August 31, 2008 has shown that HBV PreS mutations, C1653T, T1753V, and A1762T/G1764A, are associated with an increased risk of HCC (30).…”

“…In Mainland China, an endemic area with almost one third of the HBsAg carriers found worldwide (1), HBV genotypes and mutations have been investigated in a limited number of the hospital-based patients and selected geographic areas (21,22,24,25,27,31,32). However, no community-based epidemiologic study with sufficient participants has shown nationwide distribution of HBV genotypes and the prevalence of the HCC-associated viral mutations as well.…”

HLA-DPPolymorphisms Affect the Outcomes of Chronic Hepatitis B Virus Infections, Possibly through Interacting with Viral Mutations

“…HBV genotypes have distinct geographic distributions and have been shown to differ with regard to clinical liver diseases, outcomes, and responses to interferon treatment (5). In East Asia, where HBV genotypes B and C are endemic, viral factors of HBV, including genotype C infection, hepatitis B virus e antigen (HBeAg) expression, high viral load (Ͼ10 4 copies/ml), and mutations in the enhancer II/basal core promoter/precore (EnhII/BCP/PC) and the pre-S regions, as well as active hepatic inflammation contribute greatly to the development of advanced liver diseases, especially HCC (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Some of the mutations can happen years before a diagnosis of HCC is made and gradually accumulate during the progression of chronic liver diseases (9,(13)(14)(15)(16).…”